Irbesartan and Hydrochlorothiazide 150 mg; 12.5 mg Tablet, Film Coated, 30-count — NDC 63187-653-30 (Billing 63187-0653-30)

5 WARNINGS AND PRECAUTIONS • Hypotension: Correct volume-depletion prior to administration.( 5.2 ). • Impaired renal function ( 5.8 ). • Thiazide diuretics may cause an exacerbation or activation of systemic lupus erythematosus ( 5.4 ). • Acute myopia and secondary angle-closure glaucoma. ( 5.9 )

5.1Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue irbesartan and hydrochlorothiazide tablets as soon as possible [see Use in Specific Populations ( 8.1 ) ]. Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

5.2Hypotension in Volume- or Salt-Depleted Patients Excessive reduction of blood pressure was rarely seen in patients with uncomplicated hypertension treated with irbesartan alone (<0.1%) or with irbesartan and hydrochlorothiazide (approximately 1%). Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with intravascular volume- or sodium-depletion, eg, in patients treated vigorously with diuretics or in patients on dialysis. Such volume depletion should be corrected prior to administration of antihypertensive therapy.

If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

5.3Hypersensitivity Reaction Hydrochlorothiazide Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

5.4Systemic Lupus Erythematosus Hydrochlorothiazide Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

5.5Electrolyte and Metabolic Imbalances Irbesartan and hydrochlorothiazide In double-blind clinical trials of various doses of irbesartan and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 7.5% versus 6.0% for placebo; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was <1.0% versus 1.7% for placebo. No patient discontinued due to increases or decreases in serum potassium. On average, the combination of irbesartan and hydrochlorothiazide had no effect on serum potassium.

Higher doses of irbesartan ameliorated the hypokalemic response to hydrochlorothiazide. Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium. Concurrent therapy with hydrochlorothiazide may reduce the frequency of this effect.

Hydrochlorothiazide Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia.

Monitor serum electrolytes periodically. Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient. Thiazides may decrease urinary calcium excretion. Thiazides may cause… [Excerpted — this section continues on DailyMed.]

6 ADVERSE REACTIONS Most common adverse events (≥5% on Irbesartan and hydrochlorothiazide tablets and more often than on placebo) are dizziness, fatigue, and musculoskeletal pain ( 6.1 ).To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Irbesartan and hydrochlorothiazide Irbesartan and hydrochlorothiazide tablets have been evaluated for safety in 1694 patients treated for essential hypertension in 6 clinical trials.

In Studies I through IV with irbesartan and hydrochlorothiazide tablets, no adverse events peculiar to this combination drug product have been observed. Adverse events have been limited to those that were reported previously with irbesartan or hydrochlorothiazide (HCTZ). The overall incidence of adverse events was similar with the combination and placebo.

In general, treatment with irbesartan and hydrochlorothiazide tablets was well tolerated. For the most part, adverse events have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of irbesartan and hydrochlorothiazide therapy due to clinical adverse events was required in only 3.6%.

This incidence was significantly less (p=0.023) than the 6.8% of patients treated with placebo who discontinued therapy. In these double-blind controlled clinical trials, the following adverse events reported with irbesartan and hydrochlorothiazide tablets occurred in ≥1% of patients, and more often on the irbesartan and hydrochlorothiazide combination than on placebo, regardless of drug relationship: Irbesartan/ HCTZ (n=898) (%) Placebo (n=236) (%) Irbesartan (n=400) (%) HCTZ (n=380) (%) Body as a Whole Chest Pain 2 1 2 2 Fatigue 6 3 4 3 Influenza 3 1 2 2 Cardiovascular Edema 3 3 2 2 Tachycardia 1 0 1 1 Gastrointestinal Abdominal Pain 2 1 2 2 Dyspepsia/heartburn 2 1 0 2 Nausea/vomiting 3 0 2 2 Immunology Allergy 1 0 1 1 Musculoskeletal Musculoskeletal Pain 6 5 6 10 Nervous System Dizziness 8 4 6 5 Dizziness Orthostatic 1 0 1 1 Renal/Genitourinary Abnormality Urination 2 1 1 2 The following adverse events were also reported at a rate of 1% or greater, but were as, or more, common in the placebo group: headache, sinus abnormality, cough, URI, pharyngitis, diarrhea, rhinitis, urinary tract infection, rash, anxiety/nervousness, and muscle cramp.

Adverse events occurred at about the same rates in men and women, older and younger patients, and black and non-black patients. Adverse events in Studies V and VI were similar to those described above in Studies I through IV. Irbesartan Other adverse events that have been reported with irbesartan, without regard to causality, are listed below: Body as a Whole : fever, chills, orthostatic effects, facial edema, upper extremity edema Cardiovascular : flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, hypotension, syncope, arrhythmic/conduction disorder, cardiorespiratory arrest, heart failure, hypertensive crisis Dermatologic : pruritus, dermatitis, ecchymosis, erythema face, urticaria Endocrine/Metabolic/Electrolyte Imbalances : sexual dysfunction, libido change, gout Gastrointestinal : diarrhea, constipation, gastroenteritis, flatulence, abdominal distention Musculoskeletal/Connective Tissue : musculoskeletal trauma, extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, joint stiffness, bursitis, muscle weakness Nervous System : anxiety/nervousness,… [Excerpted — this section continues on DailyMed.]

7 DRUG INTERACTIONS Irbesartan Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX ‑ -2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDS, including selective COX-2 inhibitors with angiotensin II receptor antagonists, including irbesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving irbesartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonist, including irbesartan may be attenuated by NSAIDS including selective COX-2 inhibitors. Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin-receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on irbesartan and hydrochlorothiazide tablets and other agents that affect the RAS.

In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Do not coadminister aliskiren with irbesartan and hydrochlorothiazide tablets in patients with diabetes.

Avoid use of aliskiren with irbesartan and hydrochlorothiazide tablets in patients with renal impairment (GFR <60 mL/min). Hydrochlorothiazide When administered concurrently the following drugs may interact with thiazide diuretics: Alcohol, Barbiturates, or Narcotics : potentiation of orthostatic hypotension may occur. Antidiabetic Drugs (oral agents and insulin) : dosage adjustment of the antidiabetic drug may be required.

Other Antihypertensive Drugs : additive effect or potentiation. Cholestyramine and Colestipol Resins : absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Irbesartan and hydrochlorothiazide tablets should be taken at least one hour before or four hours after these medications. Corticosteroids, ACTH : intensified electrolyte depletion, particularly hypokalemia. Pressor Amines (eg, Norepinephrine) : possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal Muscle Relaxants, Nondepolarizing (eg, Tubocurarine) : possible increased responsiveness to the muscle relaxant. Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of irbesartan or thiazide diuretics. Monitor lithium levels in patients receiving irbesartan and hydrochlorothiazide tablets and lithium.

Non-steroidal Anti-inflammatory Drugs : in some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when irbesartan and hydrochlorothiazide tablets and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Carbamazepine : concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic hyponatremia.

Electrolytes should be monitored during concomitant use. • NSAIDS and selective COX-2 inhibitors: May lead to increased risks of renal impairment and loss of antihypertensive effect. Monitor renal function periodically. • Dual blockade of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. • Antidiabetic Drugs: Dosage adjustment of antidiabetic may be required • Cholestyramine and… [Excerpted — this section continues on DailyMed.]